常规的1型树突状细胞(cDC1s)在抗原交叉呈递和引发CD8+T细胞抗肿瘤免疫方面具有优势,是癌症免疫疗法的高度关注的目标。I型干扰素（IFN）是抗原交叉呈递的有效诱导剂，但是,不幸的是,显示只有适度的结果在临床上给予短的半衰期和高毒性的目前的I型干扰素治疗，这限制了IFN在肿瘤中的暴露。CD8+T细胞免疫依赖于cDC1s中的IFN信号传导,并且临床前研究表明将IFN直接靶向cDC1s可能足以驱动抗肿瘤免疫。这里,我们设计了抗XCR1抗体（Ab）和IFN突变蛋白（IFNmut）融合蛋白（XCR1Ab-IFNmut），以确定全身递送是否可以驱动cDC1s中选择性和持续的I型IFN信号传导，从而导致抗肿瘤活性，并行,减少全身毒性。我们发现，与未靶向的对照IFN相比，XCR1Ab-IFNmut融合蛋白特异性增强了肿瘤和脾脏中的cDC1激活。然而,使用XCR1Ab-IFNmut融合的多种治疗可产生稳健的抗药物抗体(ADA)和药物暴露损失.使用其他cDC1靶向Ab-IFNmut融合体，我们发现，将IFN直接定位到cDC1s激活它们促进ADA反应的能力，无论cDC1靶向抗原。ADA的开发仍然是免疫治疗药物开发的主要障碍，并且控制人类ADA反应发展的细胞和分子机制尚未得到很好的了解。我们的结果揭示了cDC1在ADA生成中的作用，并强调了将免疫刺激剂靶向该细胞区室的潜在ADA挑战。
Conventional type 1 dendritic cells (cDC1s) are superior in antigen cross-presentation and priming CD8+ T cell anti-tumor immunity and thus, are a target of high interest for cancer immunotherapy. Type I interferon (IFN) is a potent inducer of antigen cross-presentation, but, unfortunately, shows only modest results in the clinic given the short half-life and high toxicity of current type I IFN therapies, which limit IFN exposure in the tumor. CD8+ T cell immunity is dependent on IFN signaling in cDC1s and preclinical studies suggest targeting IFN directly to cDC1s may be sufficient to drive anti-tumor immunity. Here, we engineered an anti-XCR1 antibody (Ab) and IFN mutein (IFNmut) fusion protein (XCR1Ab-IFNmut) to determine whether systemic delivery could drive selective and sustained type I IFN signaling in cDC1s leading to anti-tumor activity and, in parallel, reduced systemic toxicity. We found that the XCR1Ab-IFNmut fusion specifically enhanced cDC1 activation in the tumor and spleen compared to an untargeted control IFN. However, multiple treatments with the XCR1Ab-IFNmut fusion resulted in robust anti-drug antibodies (ADA) and loss of drug exposure. Using other cDC1-targeting Ab-IFNmut fusions, we found that localizing IFN directly to cDC1s activates their ability to promote ADA responses, regardless of the cDC1 targeting antigen. The development of ADA remains a major hurdle in immunotherapy drug development and the cellular and molecular mechanisms governing the development of ADA responses in humans is not well understood. Our results reveal a role of cDC1s in ADA generation and highlight the potential ADA challenges with targeting immunostimulatory agents to this cellular compartment.
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